**Abstract**

Modern studies in the world have attached high priority to the role of genetics in human psychosocial stress. People who have strong biochemical responses to stress are more inclined to develop acute and posttraumatic stress disorders. Why do such unusually strong biological reactions occur in certain people? Psychogenetics focuses on many aspects: personality traits that can affect human behavior directly. Their individual variability has been found to be a genetic trait. At present we already know a number of genes, certain allelic variants and genotypes associated with some neuropsychological characters. Among these are genes encoding intracellular and plasma protein neurotransmitter transporters and their receptors; to date, there are only several dozen genes. Of particular interest are dopaminergic system genes. However, information about the polymorphism of known genes associated with personality traits is quite limited and contradictory for open population. Under these circumstances, the chapter is devoted to the association of polymorphisms of candidate genes of the dopaminergic system with anxiety in the open population.

**Keywords:** DRD4 gene, DAT gene, anxiety, psychosocial factors, open population

### **1. Introduction**

An individual's unique pattern of behaviors, feelings and thoughts is his or her personality expression, which is a strong predictor of the physical, mental and social aspects of current and future health across the lifespan [1]. The psychobiological model of personality Cloninger C.R. (1987) became the prerequisite for the genetic basis search of personality and temperament where temperament traits are correlated with certain biochemical systems in the brain. Cloninger C.R. identified four dimensions for temperament: 'harm avoidance', 'novelty seeking', 'reward dependence' and 'persistence'.

People with high grades on the 'novelty seeking' scale are impulsive, irritable, and tend to break rules blocking access to what they believe will bring satisfaction or allow them to shake themselves. On the other hand, there is conventionality, adherence to rules. Cloninger C.R. connected the 'novelty seeking' - with the

dopamine system [2]. Dopamine is a neurotransmitter that provides neurochemical transmission in the nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular dopaminergic systems in mammals. These brain structures play a vital part in the implementation of psychomotor, cognitive, neuroendocrine functions [3]. Relationship between 'novelty seeking' and dopamine system has been found: an association of temperament with genetic polymorphism encoding the fourth type dopamine receptor (DRD4) was established [4].

The dopamine D4 receptor gene is located on chromosome 11 (11p 15.5) [5]. The human D4 gene has the regions homologous to the regions of the human D1 and D2 genes and other G-proteins and contains 7 transmembrane domains [6]. Unlike the D2 gene containing 7 exons, the D4 gene contains 5 exons. The encoded polypeptide has a molecular weight of 41,000 Da and consists of 387 amino acids. Currently, four polymorphic regions have been identified in the dopamine D4 receptor gene. Three of these polymorphic alleles in humans are not widely distributed. The widespread polymorphism of variable numbers of tandem repeats 48 bp (VNTR) in exon 3 of the D4 gene is most important. The third exon of the dopamine D4 receptor gene contains alleles with a variable number (2–10) of imperfect DNA repeats 48 bp long encoding the region in the third cytoplasmic loop of a 16 amino acid with a general consensus PXAPXLPXXPXGXXCA [7]. A different number of amino acids in the cytoplasmic loop affects the conformation of transmembrane domains and changes the characteristics of ligand binding. Sequenced at least 19 monomers of nucleotide sequences of imperfect repeats in 48 bp and 25 variations of a polymorphic region containing from 2 to 10 repeats [6]. The study on the global frequency distribution of allelic variations of the D4 gene [8] showed that in the healthy population the most common is 4-repeat allete (D4.4) (global frequency in the world is 64.3%). The D4.4 allele is found in all populations with a frequency of 16–96%. The second most frequent variant was 7 repetitions (D4.7) (global frequency in the world 20.6%), which is quite frequent in the American population (average frequency 48.3%) and is rarely represented in populations of East and South Asia (average frequency 1.9%). 2-repeat allete (D4.2) is the third most frequent (global frequency in the world is 8.2%). More often this allele is found in populations of East and South Asia (average frequency 18.1%) and is almost absent in American and African populations (average frequency 2.9% and 1.7%, respectively). The universality of the polymorphism (three repeat-number alleles) indicates that this polymorphism arose before the global dispersion of modern humans [9].

Unused dopamine is moved back to the presynaptic neuron or oxidized by enzymes in the synaptic cleft. Protein dopamine transporter (DAT) provides a reuptake of the mediator in the synaptic cleft. The gene for the DAT1 protein (dopamine transporter) is localized to chromosome 5p15.3, consists of 64 thousand nucleotide pairs, contains 15 exons and 14 introns. Analysis of the 3′untranslated region revealed the presence of the polymorphic locus in it associated with a different number of repeats of 40-nucleotide sequence, repeated from 3 to 11 times [10].

VNTR allele frequencies of the DAT gene in representatives of different ethnic groups differ significantly. The 10-repeat allele has been indicated as the most represented one in all studied populations. Its frequency ranges from 60% (Italians) to 93% (Japanese). The frequency of the 9-repeat allele, which is the second most frequent allele, varies from 4.2% (Japanese) to 39% (Italians). The remaining alleles are present in all populations, but the frequency is less than 3%. The shortest variation with 3 repeats has been found with a low-frequency only in white Americans and African Americans [11].

#### *Association of Personal Anxiety with Dopamine Receptor D4 (DRD4), DAT Genes Polymorphism DOI: http://dx.doi.org/10.5772/intechopen.94386*

As in the case of the D4 gene, the DAT gene polymorphism can be associated with some pathological conditions in the pathogenesis, which play the main role in disorders of dopamine metabolism. However, the results of the study on the association between DAT and the 'novelty seeking' are inconsistent so far [12].

Anxiety may be due to neurotransmitter disorders: impaired dopamine synthesis. Nevertheless, the search for a relationship between disturbing traits and the DRD2, DRD3, DRD4, DAT1 genes has yielded conflicting results at present [13].

There is a wide range of convincing clinical studies in laboratory animals that indicate a disorder in the dopaminergic system in depression [14]. López León et al. (2005) performed a meta-analysis of 12 studies of VNTR of the DRD4 gene polymorphism with depression. According to the results of the study, it turned out that the 'short' allele 2 is associated with depression [15].

Most people believe that a state of vital exhaustion arises from long-term psychosocial problems they are not able to solve [16]. As has been shown, dopamine is involved in certain responses to surrounding stressful events [17], and some dopamine reuptake inhibitors have an antidepressant effect [18]. It is still open to question whether the development of vital exhaustion, as a variant of minor depression, is due to certain changes in the dopaminergic system.

We note that at present, predominantly molecular genetics "leads" psychological research to find associations of personality traits, as well as affective disorders. Given these circumstances, the chapter is devoted to the association of candidate gene polymorphisms in dopaminergic system with psychosocial risk factors.

## **2. Materials and methods**

The research of the association of candidate gene polymorphisms with psychosocial factors was carried out on the basis of a large-scale epidemiological study performed as part of the III screening of the WHO MONICA program (Multinational Monitoring of Trends and Determinants of Cardiovascular Disease) in 1994 [19]. We examined men 25–64 years of age, residents of a district in Novosibirsk. The representative sample was generated according to the requirements of the protocol of the MONICA program [19] on the basis of electoral lists using a random number table. 657 men were examined (average age 44.3 ± 0.4 years). The response was −82.1%.

### **3. Psychosocial testing**

The Spielberger test was used to assess anxiety level. The result was interpreted as follows: up to 30 points – mild anxiety level; 34–45 points – moderate anxiety level, 46 and above – severe anxiety level [20]. To evaluate depression, we used the form of the depression scale - the MOPSY test (Depression Scale), consisting of 15 questions. For each question there are 2 answers given: 'agree', 'disagree'. The severity of depression was assessed as no depression (No D), moderate (Mod. D), major (Major D). To assess vital exhaustion, the MOPSY test [19], consisting of 14 statements, was used. For each question there are three answers given: 'yes', 'no', 'I don't know'. The level of vital exhaustion was regarded as: no vital exhaustion, vital exhaustion (average, high). Questionnaires were filled out by the participants. The methods were strictly standardized and complied with the requirements of the protocol of the MONICA project. Material processing performed in

Helsinki (Finland). Quality control was carried out in MONICA quality control centers: Dundee (Scotland), Prague (Czech Republic), Budapest (Hungary). The presented results were found to be satisfactory [19].
